People with schizophrenia stop taking their antipsychotics for a wide range of reasons (e.g. debilitating side effects or a belief that they will not help them), but when they do health professionals often find it extremely difficult to care for these patients, because the alternative treatment options available to them are very limited.

Of course, patients not taking antipsychotics often disappear from mental health services because they are not engaged in treatment and sometimes live in fear of being sectioned and forced to restart their medication.

We know from the biggest trial to date comparing antipsychotics, that as many as three quarters of patients with schizophrenia discontinued their drugs over 18 months (Lieberman et al, 2005), so this is a widespread problem and alternative treatments are badly needed.

To date, the research looking at combining antipsychotics with CBT for schizophrenia has brought back mixed results. At least one meta-analysis supports the idea that the two treatments can work safely and effectively alongside each other, whilst various other reviews and analyses are less encouraging.

A new trial published today in The Lancet offers a chink of light for people with schizophrenia who do not take antipsychotics as (according to Oliver Howes who has written an attached commentary) it provides:

proof of concept that cognitive therapy is an alternative to antipsychotic treatment.

Methods

The research team led by Prof Anthony Morrison from the University of Manchester conducted a single-blind, pilot randomised trial that recruited people with schizophrenia who had decided not to take antipsychotics.

74 people were randomised to one of two groups:

Treatment as usual (TAU)

Cognitive therapy plus TAU

The primary outcome was total score on the Positive And Negative Syndrome Scale (PANSS), which was measured at baseline and then every 3 months until 18 months. The PANSS is a clinician-administered semi-structured interview assessing positive symptoms (e.g. hallucinations, delusions, suspiciousness, paranoia), negative symptoms (e.g. lack of initiative, social withdrawal, lack of expression, emotional withdrawal), and general psychopathology (e.g. depression, anxiety, poor insight, guilt).

Data were analysed according to a predetermined plan which meant that investigators could not ‘cherry pick’ good outcomes in favour of their treatment; all amendments to the study plan were documented in the report; assessments of outcome were taken by assessors who did not know which therapy participants were receiving (rater blindness).

Patients could not be blinded in this study. Indeed, it’s worth noting that there are many factors that make this trial very difficult to carry out, but overall the authors should be commended for publishing a well conducted piece of research.

Results

The trial reports that:

Compared to TAU, cognitive therapy is associated with important treatment signals including a reduction in psychotic experiences such as hearing voices and paranoia and an improvement in day to day social functioning

Mean PANSS total scores were consistently lower in the cognitive therapy group than in the TAU group, with an estimated between-group treatment effect size of -6·52 (95% CI -10·79 to -2·25; p=0·003)

This equates to a standardised effect size (Cohen’s d) of 0·46

However:

Analysis of the effect sizes for CBT vs controls at 9 months reveals no significant differences on PANSS total, PANSS positive or PANSS negative. This finding is consistent with the results of the recent meta-analysis published in the British Journal of Psychiatry (Jauhar et al, 2014)

Furthermore, the baseline and 9 months PANSS data for the unmedicated TAU group show a symptom improvement that is just as large as the CBT group at 18 months. In other words, the end of study finding for CBT is no bigger than the natural levels of fluctuation (improvement) that can be seen in the data for the unmedicated patients

CBT did not reduce distress at all (for delusions or hallucinations), self-rated recovery, depression or anxiety

Can we be sure that the trial results represent more than just natural fluctuation?

Conclusions

The lead researchers summarised their findings quite simply by concluding that:

Cognitive therapy significantly reduced psychiatric symptoms and seems to be a safe and acceptable alternative for people with schizophrenia spectrum disorders who have chosen not to take antipsychotic drugs.

One of our most interesting findings was that when given the option, most patients were agreeable to trying cognitive therapy. If someone is on antipsychotics they should not just suddenly stop taking them as there is a major risk of relapse. Medical advice should always be sought if you are considering stopping your medication.

The Mental Elf team believes that this is an overstatement of the evidence as reported in this article, for the reasons set out below.

Limitations

The patients in this trial were a highly selected group who were willing to try CBT. Clinicians will tell you that schizophrenia patients who won’t take antipsychotics are often difficult to engage in any form of therapy.

The study did not include an active comparison group such as befriending or supportive therapy.

Arguably to establish effectiveness of CBT a third placebo arm would have been ideal. This would be along the lines of supportive/non-specific counselling in addition to TAU, so as to show that it was CBT alone (and not the regular meeting with a professional to discuss symptoms) that led to the overall change in PANSS.

The issue of blinding is problematic, and cases where blinding was broken continued to be included in the study; albeit with attempts made to mask this unblinding. Patients could not be blinded to their group, and biases will have been introduced by this.

Not all patients were accounted for at the conclusion of the trial. This crucial issue was difficult to appraise because different numbers of patients appeared to be included for different outcomes. Furthermore, different numbers of patients were included for different time periods.

However, for all outcomes, drop out was high by the end of the study: 30% in the CBT group and 32% in the TAU group. High enough that we’d expect it to affect our assessment of the effectiveness of the treatments.

Serious adverse events occurred in more than 10% of patients, mostly in the TAU group, which suggests that lack of medication is not an acceptable ‘treatment’.

A significant number of the patients in both groups were given antipsychotics during and after the trial, and this confounder does not seem to have been clearly addressed. Presumably these subjects should have been removed from the trial as it was specifically looking at those who were unmedicated.

The trial did not include any information on the costs of treatment, which is a significant omission considering that patients who completed the 18 months of therapy would have received 26 hours of very costly CBT.

Clearly, there is a risk of bias in these results and they need to be replicated in a bigger trial before changes are made in clinical practice. Professor Morrison and colleagues are about to commence such a study in Manchester to compare cognitive therapy alone with antipsychotic medication alone and with a combined treatment in people with schizophrenia spectrum disorders.

Moreover, perhaps the next study should be conducted by another research group? After all, the authors of this study are the top cognitive therapists for psychosis in the country, who have published extensively on the subject. It might also be sensible to compare CBT with other, more diverse approaches such as social support, nurse visits or education in any future studies. Surely we would then be better placed to know the true value of CBT for this population?

The results of this trial are not as clear cut as the press release would have you believe

Comments from experts in the field

As you would expect, this new RCT has generated a great deal of interest from the mental health community.

The Morrison study is particularly interesting as it offers CBT to people who are engaged with mental health services, but have chosen not to take any medication. Most people who do not take medication usually stay as far away from mental health services as possible in case they ‘get sectioned’ and are made to take the drugs, so their sample is narrowly defined and it may not generalise to people who completely drop out of contact.

Prof Shitij Kapur, Professor of Schizophrenia, Imaging and Therapeutics, and Head of School at the Institute of Psychiatry, King’s College London, said:

This is an important trial that shows that CBT works – and works for a very difficult to treat population – the patients who do not take drugs. This is important as clinicians can often get nihilistic about patients who are “non-compliant”. What the paper tells us is that we can engage psychotic patients who do not take antipsychotics and deliver clinical benefits.

This approach is certainly worth exploring further. This is especially so because we are realising that long-term antipsychotic treatment may cause receptor changes that make it difficult to stop the drugs, and consequently psychiatrists may become more cautious about the long-term prescription of antipsychotics.

Prof Keith Laws, Department of Psychology, University of Hertfordshire, said:

This study by Morrison and colleagues provides novel insights, but not necessarily those alluded to by the authors. Crucially, the symptom change they attribute to CBT is no greater than the level of ‘natural’ symptom fluctuation observable in the controls (e.g. between baseline and 9 months) – so it’s quite possible that what Morrison et al are documenting is simply the ‘natural fluctuation’ of symptoms that occurs in unmedicated patients and nothing at all to do with CBT.

André Tomlin is an Information Scientist with 20 years experience working in evidence-based healthcare. He's worked in the NHS, for Oxford University and since 2002 as Managing Director of Minervation Ltd, a consultancy company who do clever digital stuff for charities, universities and the public sector. Most recently André has been the driving force behind the Mental Elf and the National Elf Service; an innovative digital platform that helps professionals keep up to date with simple, clear and engaging summaries of evidence-based research. André is a Trustee at the Centre for Mental Health and an Honorary Research Fellow at University College London Division of Psychiatry. He lives in Bristol with his wife, dog and three little elflings.

Follow me here –

I am an information scientist with an interest in making knowledge from systematic research more accessible to people who need it. This means you. I've been attempting this in the area of Evidence-Based Health Care since 1995. So far the results have been mixed. For some reason we expected busy clinicians to search databases and appraise papers instead of seeing patients. We also expected publishers to make the research freely available to the people who paid for it.. Ha! Hence The National Elf service.

honestly you reanalysed the completer data from means and sds and prioritised this over the analysis provided by the authors which included a prof of medical statistics – and asked KEITH LAWS for his opinion? This is laughable stuff.

“@Mental_Elf Prof Law’s point is good….” There is no way Keith Laws would ever accept cbt having benefits for anyone with psychosis. The man’s on a frenzied crusade – everyone outside of his twitter cabal knows it.

I appreciated this analysis of the article, but think it was still a bit too mild. I have made my own analysis of the article, and here are my conclusions about the specifics, and a conclusion. It is a difficult situation to be in. With all the experience acquired through doing this trial, warts and all, it would be desirable if this group would do more work. However, if the trial is not regarded as “successful”, funding may be (even) hard(er) to get. Scientifically inconclusive trials are as important as ones with a positive result. I can understand the authors very much wanting to present the conclusions as they did. And more research into therpy for schizophrenia, well-designed research, is very valuable.
Summary
I conclude from a careful analysis of the Lancet article that enough information is provided to be able to say that the conclusions reported are not supported by the evidence of the study.
The major reasons are that the attrition is too large for comfort with the 18 months outcome, whereas the 9 months outcome is inconclusive. In addition the administration of antipsychotics may have been an obvious possible alternative explanation for the 18 months result favouring cognitive therapy (CT). There are many unresolved issues, including ones that the protocol had announced would be reported on. There are unreported unknowns about the composition of the trial groups, the attrition was uncomfortably large, the behaviour of PANSS symptoms for the TAU group over the 18 months is unexplained, and the relationship of the full group to the core construct of schizophrenia is unclear. Overall this is a disappointing conclusion to draw.
An additional significant criticism of the reporting of the trial is the emphasis on conclusions to be drawn from it about the attractiveness of cognitive therapy as an alternative to antipsychotics. If that were the purpose of the study, there should have been at least two arms, one with CT and the other with the administration of antipsychotics. This part of the suggested conclusions is not sufficiently related to the design of the trial.

Unclear focus
In the Lancet article there is a lot of discussion about cognitive therapy (CT) as an alternative to anti-psychotics. The study is flawed, as it cannot make up its mind what it is trying to determine. It does not compare with a clear placebo; and it does not compare with antipsychotic treatment. If the point is to suggest that CT is more effective than antipsychotics, this should have been reflected in the study design. As it was not in the design, the conclusions in that direction are not supported by the study. This is a fundamental of the construction of randomised controlled trials (RCTs) that provide usable research evidence.
Even on its own terms the study’s design as implemented is incoherent: it supposedly was a comparison between CT + TAU and TAU for trial subjects who were not using antipsychotics, but during the trial a considerable number of participants were prescribed antipsychotics: in each of both arms ten participants were prescribed antipsychotics, out of the 17 in each arm which were followed up for 18 months.
It is made clear that all follow-up of the CT group has been done while CT is still being made available, at least on a once per quarter basis. This means that there is no follow-up of what happens to the outcome after the treatment is ended; this was planned in the protocol, but no less undesirable for that. Presumably there was no pattern to the provision of treatment in the TAU arm. Additionally, it is a question to be asked why the PANSS scores in the TAU arm had such a pronounced pattern over the term of the trial, declining from 73 at the start to 63 at 9 months (a very big shift), and going up again to reach 71 at the 18 months stage. What is seen as a possible explanation for this pattern, if the treatment has been held constant? This should have been discussed at the minimum.

Selection of people
There were major problems with the composition of the participant groups. Apart from the general question-mark that it seems unlikely and in need of explanation how this large group of treatment-positive subjects could be found, when usually a refusal to take antipsychotics goes along with a reluctance to engage with psychiatric services overall, there are other questions:
• The protocol specified at first that substance use disorder was a reason for exclusion (a common restriction for this kind of trials), but the article says that this was subsequently (no date given) changed. This is a real problem, as it leads to the question how participants with comorbid substance use disorder were divided over the arms of the trial, and what treatment they received related to their substance use disorder. This problem is not reported on, analysed or discussed. Presumably, if this would have been negligible in numbers terms, it would have been easier to exclude them as participants.
• Not all participants were diagnosed with schizophrenia. It would have been normal to state how the participants were divided (for each arm!) over the four categories, schizophrenia, schizoaffective disorder, delusional disorder and “meeting entry criteria for early intervention for psychosis service”. The presence of participants with delusional and with schizoaffective disorder, if significant, also raises questions as to the homogeneity and comparability of the group(s), as they have by their diagnostic definition a rather different profile than standard schizophrenia, which is already a quite varied syndrome as it is. The protocol states that of the total group of 74 participants 59% derived from the “Early intervention in psychosis service”. This might or might not coincide with those for whom a diagnosis of schizophrenia could not be made. What is important is that there is no further reporting about how this subgroup was divided between the two arms, and how it behaved under the very significant attrition that took place.
• Schizophrenia is a diagnosis with a marked profile over the life-span: it has a peak age of onset between 20 and 24 years. As the reported age range of participants varies between 16 and 65 years, it would have been better to have a clear idea of the range of the participants by age group, and how this developed under the very significant attrition during the trial.

Time frame for evaluation
It is reported that it was not possible, for budgetary reasons, to give the same follow-up to all participants. This makes it more difficult to evaluate the conclusions. The reported significant difference in total PANSS scores between CT + TAU and TAU obtains at 18 months, not for the 9 months’ comparison. At the 18 months’ stage only 17 remained in each arm of the original 37, an uncomfortably severe attrition of over 50%. At 9 months the attrition was still significant, but lower — to 22 / 23 in the two arms from the original 37 each. The conservative method to deal with this would have been to report only the results for the period over which all participants treated had been evaluated — but in that case the trial would have reported CT as ineffective statistically.

What was the complete care package provided?
It appears a lot of services were provided in both arms of the trial, without a clear view what these might be in total, or what the differences might be. In any case what was provided was not treatment as usual, but “enhanced treatment”. It appears a lot of extra care was given beyond what services normally provide. Given the average age of the participants, considerably over the peak age of onset of schizophrenia, this would have been clear to many of the participants.
In any case what is reported is that the package provided includes warm face-to-face contact, supportive listening, and crisis management. It also included prescription of antipsychotics (10 people in each arm), and antidepressants. In addition it appears that a certain number of participants were in treatment at other centres, and there is the question of the treatment for those with comorbid substance use disorder.
Another question I have is what happened in the initial “recruitment period”. I have the impression that treatment only started around Aug 2011, but participants were being recruited from Feb 2010 onwards. It is not reported what support or treatment was provided to these subjects in the intervening waiting period, and what they were told.

Insufficient blinding
The blinding was only one-sided, in that the assessors of progress were meant to be in the dark about the allocation. However, this blinding was broken (and somewhat remedied) about 13 times, out of the total 45 (evaluated for 9 months) or 34 (evaluated for 18 months) participants.
However, it wasn’t a clear-cut situation of the participants and the therapists not being blinded, and only the assessors who were. Since there was so much “other care” being provided, and it appears that the small group of people doing the study were involved in everything, it may have also been that all or most other care providers knew whether a participant was having CT or not, thus undermining – statistically – the interpretation of the trial outcome.

Incomplete analysis
A number of issues could have been reported in, or even analysed, but were not:
• The protocol (according to the version published online Feb 2013 – Morrison et al (2013) in Psychosis) stated that the study would “examine … the sensitivities of all treatment effect estimates to missing outcome data from patient drop-out”, “any differential effects of initiating medication will be controlled for”, and site effects would be analysed. It mentions the issue of therapist effects. It also states that an economic analysis is “planned”. None of these appear to be fully reported on in the Lancet article.
• Sensitivity to a number of age groups should have been analysed, given the clear age structure of schizophrenia.
• The confounding with substance / alcohol use disorder should have been mentioned and analysed.
• The administration of antipsychotics is all the more important, as they were significant in numbers (10 out of 17 of each arm for the 18 months group; 8/9 in the two arms out of the 22/23 in the two arms), and may have influenced the 18 months outcome: inspection of all lines of Table 4 shows that the antipsychotics were more used on the improved than on the deteriorated side of the trial arms, but at the 18 months outcome stage they clearly show more correlation with the improved outcome of the CT+TAU group than for the TAU group. If you take the existence of that correlation seriously, given that it is unlikely that symptom improvement would lead to more antipsychotic usage, there is at least a possibility that the antipsychotic administration had something to do with the symptom improvement. In any case, statistically it seems that this cannot be excluded.

It’s clear there are a few here with axes to grind, but perhaps some of the gushing reports of this study and some of the critiques are a little overstated.

The authors conclude that this needs more research (actually not a trivial conclusion), and that’s probably the most one should draw. There are some major limitations, but I’m not sure one can dismiss this study out of hand.

I’m not sure the science on this is helped by making fairly definitive claims about other explanations for the results (e.g. fluctuations of symptoms) when there just isn’t the evidence there for such a claim. The results presented in the paper don’t provide any basis for this claim, so I’d hold fire on being so definitive on this until data that actually support such alternative explanations is presented.

You accuse us of being evasive, but actually we have answered all of your questions in a calm and measured way.

I’m delighted to see that you’ve taken Douglas’ advice and re-read our blog. I shall interpret your lack of response to his comments as tacit acceptance of his clear and well made points.

You ask why we think that future research should be conducted by another group. There are two main reasons for this:

1. Firstly, it’s important that research reflects the real-world experience as much as possible, as that makes it possible to implement the findings of studies in practice. The leading CBT therapists in the country are not representative of CBT therapists as a whole. Now clearly it may be that Prof Morrison et al are planning to conduct a new study involving a representative sample of therapists. We don’t know, but we look forward to hearing more on that front in the near future.

2. Secondly, there’s the issue of conflict of interest. Prof Anthony P. Morrison and colleagues have published many books and research articles on cognitive therapy, so we would argue that they have a vested interest in future trials coming out in favour of CBT. We would all be concerned if a drug trial was conducted or sponsored by a pharmaceutical company selling the medication, so we should be careful to apply this same principle when appraising trials of talking treatments.

You also ask for links to other examples of this careful evidence-based approach to critically appraising research that we are displaying. I suggest you read some more of the blogs on this website, which all aim to highlight mental health research, policy and guidance in an unbiased and clear way. Really it’s your responsibility to do some research yourself and not insist that we do it all for you.

We are independent from industry, but also from any of the professional camps that exist within mental health research and practice. I did ask Keith Laws to comment on this new trial, but I also asked 14 other experts in the field who represent a broad range of views and professional backgrounds.

I look forward to hearing other views on this issue and I hope that all future discussions take place in a way befitting people who have patient wellbeing as their main focus.

“This study provides some evidence that cognitive therapy (CT) may be helpful for some people with a schizophrenia spectrum disorder. However, the benefits seen – as measured on the rating scale (PANSS) – are small.
The study design has strengths in that it attempted to blind the assessors as to which treatment the participants were receiving. It also recruited participants who did not want to take antipsychotic medication and had not done so for six months before the study.
However, 10 people in each group did take antipsychotics during the trial. This complicates the results, as it is not clear whether the improvements were as a result of the CT, the medication or a combination of both.
A further point that the researchers raise is that it is not clear whether the specific type of talking therapy is important, or whether the contact time, warmth and empathy that was received in the CT group was the factor that made the difference.
Schizophrenia spectrum disorders cover a wide range of symptoms and each person has a different individual experience of their illness. This study contributes to previous research, which has shown that CT can be beneficial for people with the condition.
However, importantly, it does not show that it is better or equivalent to antipsychotic medication. The participants continued to have moderate levels of illness despite receiving therapy.
If you are taking medication for a schizophrenia spectrum disorder, it is important that you do not suddenly stop. Doing so could lead to a sudden worsening of your symptoms. Tell your care co-ordinator or GP if your side effects become severe. There may be an alternative antipsychotic you can take or additional medicines that will help you deal with the side effects.”

I spoke to a person yesterday who has schizophrenia, and she credits CBT with much of her current recovery. Although I have bipolar disorder, I too have found CBT to be invaluable in my “remission”. (BTW we both continue to take antipsychotic meds.) I am eager to see the results of a follow-up study, as I do not see the authors’ summary as being reflective of the data in the study.

Unfortunately we have had to ban ‘Exasperated’ from posting further comments on this blog. We did not take this decision lightly, but a number of posts made by him/her this afternoon are personally attacking named individuals and we will not tolerate this kind of behaviour.

We hope that this discussion can continue in an open and thoughtful manner and does not degenerate into a series of verbal assaults.